Bis- and mono-quaternary salts of 1-(cyclicamino)cyclopropacycloalkanes



XR 3546233 EX mm. W... ...cnt Oflice 3,546,233 Patented Dec. 8, 1970 3,546,233 BIS- AND MONO-QUATERNARY SALTS 0F 1-(CY- 'CLICAMINO)CYCLOPROPACYCLOALKANES Jacoh Szmuszkovicz, Kalamazoo, and Elisabeth Cerda, Portage, Mich, assignors to The Upiohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing. Filed May 15, 1967, Ser. No. 638,562 Int. Cl. C07d 29/10 U5. CL 260-293 6 Claims ABSTRACT OF THE DISCLOSURE Bisquaternary ammonia compounds of the formula and mono-quaternary ammonia compounds of the formula wherein R is polymethylene of 3 to 7 carbon atoms, R is alkyl of not more than 2 carbon atoms, n is zero; or an integer not greater than 1, R; is lower alkylene of from 2 to 6 carbon atoms, X is halogen and Y is an anion." These compounds are useful as disinfectants.

BRIEF SUMMARY OF THE The invention relates to bis-quaternary ammonium compounds of the formula and mono-quaternary ammonium compounds of the formula R at) wherein R is polymethylene of 3 to 7 carbon atoms, R, is alkyl of not more than 2 carbon atoms, n is zero or an integer not greater than 2, R; is lower alkylene of from 2 to 6 carbon atoms, X ishalogen, and Y is an anion. The

novel compounds of the invention wherein X is halogen are prepared by a process illustrated by the following equation wherein R, R R n, X and Y are the same as above.

Compounds of FormuIaXIIIc are prepared from compounds of XIIIb by replacing the ionic halogen (X-) of compounds of Formula XIHb by metathesis.

DETAILED DESCRIPTION The starting l-aminocy'clopropacycloalkane, Formula II, can be prepared from the corresponding cyclopropacycloalkane-l-carboxylic acid:

by converting a carboxylicgroup to an amino group. Any

of several well known reactions can be used for this purpose, for example, the Cii'rtius reaction, the Hofiman neaction, the Losen reaction ior the Schmidt reaction (Surrey, Name Reactions in Organic Chemistry, 2nd Ed., 1961, Academic Press) or the Weinstock modifications of the Curtius reaction fweinsto'c k, J. Org. Chem. 26, 3511 The starting cyclopropacycloalkane-l-carboxylic acids of Formula III can be prepared by reacting a cycloalkene wherein R, is ethyl and hydrolyzing to the acid, Formula III, or with diazoaoetone to form a ltetone of the formula:

l COCH:

3 which is then oxidized to the desired cyclopropacyclo- .alkane-l-carboxylic acid. Meinwald et al., I. Am. Chem.

85, 582-585 (1963). An advantage of this processis that it produces exclusively, or almost so at least, the exo form which can be represented by the following formula:

A N R; vv

An alternative process produces predominately the endo form:

VII

It comprises a borohydride hydrogenolysis of a l,1-bis (cyclicarnino)cyclopropacycloalkane of the formula:

which in turn can be prepared by reacting a 2-halocycloalkanone with a base of the formula These two processes, therefore, complement one another in providing a facile synthesis of both the endo and exo forms of 1-(cyclicamino)cyclopropacycloalkanes.

The process of the invention can also be used, if desired, for producing 1 endo (cyclicarnino)cyclopropacycloalkanesQ'For example, bicyclo[3.1.0}hexane-6-endti-carboxylic acid (Meinwald et al., loc. cit.) can be converted by the procedures outlined above to d-endo-aminobicyclo [3.1.9]hexane which in turn by the procedures outlined aboveis converted to 6-endo-(cyclicamino)bicyclo[3.1.0] hexan e[ l-endo- (cycloicamino) cyclopropacyclohexane] The endo acid, for example, bicyclo[3.l.0]hexane-6- endo-carboxylic acid, can be converted to the exo form by esterify ng, for example, with diaziomethane, heating in ethanol in the presence of sodium 'ethoxide to convert to the exo ester and hydrolyzing this'ester. The exo form can also be converted to the endo form by the same process but' the yield is low because the equilibrium favors the exo form.

A further advantage of the process of the invention is that useful by-products are produced. For example, when the acid azide of a cyclopropacycloalkane-1-carboxylic acid of Formula IH is alcoholized,'for example with an allranol, to a carbamate of formula:

NHCOORQ where R; is the radical of the alcohol used in the alcoholysis, for example, lower alkyl, such as methyl, ethyl, propyl, butyl, isobutyl and the like, there is also obtained a urea of the formula:

The urea of Formula X can be converted to an isocyanate of the formula:

\g/cu P 460 by phosgenating it to form an allophanyl chloride of the formula:

r- R ah rm r u XII ' a hypoglycemic agent.

Also'when an amine of Formula H is reacted with a dihalide of the formula X-Rg-X, there are also obtained bisquat'ernary ammonium compounds of the formula:

and mono-quaternary ammonium compounds of the formula:

R l, )n

Xlllb The ionic halogen (X-) can be replaced by metathesis by other anions, for example, the anions of the acids listed hereinafter. The monoand bis-quaternary ammonium compounds have antibacterial properties, making them useful as disinfectants.

The conversion of the 1-aminocyclopropacycloalkanes to l-(cyclicamino)cyclopropacylcloalkanes is efiected by heating the free base l-aminocyclopropacycloalkane with a dihalide of the formula XR;-X as described above in an inert solvent in the presence of a scavenger for the hydrogen halide liberated, for example, an inorganic base such as alkali metal carbonates and hydroxides, or organic tertiary bases such as triethylamine and pyridine. An excess of the dihalide is advantageously used and the reaction mixture is heated to between about 50 C. and about 150 C. The solvent, for example, can be ether, acetone, methanol, ethanol, dioxane, tetrahydrofuran, or dimethylformamide. An excess of the dihalide can replace the solvent wholly or in part.

Suitable starting cyclopropacycloalkane l-carboxylic acids of Formula 111 include: bicyclo[3.1.0]hexane-6- exo-carboxylic acid, bicyclo[4.1.0]heptane-7-exo-carboxylic acid, bicyclo[5.1.0]octane-8-exo-carboxylic acid, bicyclo[6.1.0]nonane-9-exo-carboxylic acid, bicyclo[7.1.0] decane 10-exocarboxylic acid, bicyclo[3.1.0]hexane-6- endo carboxylic acid, bicyclo[4.1.0]heptane-7-endo-carboxylic acid, bicyclo[5.1.0]octane-8-endo-carboxylic acid, bicyclo[6.1.0]nonane-9-endo-carboxylic acid, and bicyclo [7.1.0]decane-10-endo-carboxylic acid.

Following the procedures outlined above there are obtained the following Formula H l-aminocyclopropacycloalkanes: 6 exo aminobicyclo[3.1.0]hexane, 7 exoaminobicyclo[4.1.0]heptane, 8 exo-aminobicyclo[5.l.0] octane, 9-exo-aminobicyclo[6.1.0]nonane, 10-exo-aminobicyclo[7.1.0]decane, 6 endo aminobicyclo[3.1.0]hexane, 7 endo-aminobicyclo[4.1.0]heptane, S-endo-aminobicyclo[5.1.0]octane, 9-endo-aminobicyclo[6.1.0]nonane, and lo-endo-aminobicyclo[7.1.0]decane.

Following the procedure outlined above there are also obtained the following ureas of Formula X: 1,3-bis(bicyclo[3.1.0]hex 6-exo-yl)urea, 1,3 bis(bicyclo[4.1.0] hept 7 exo-yl)urea, 1,3-bis(bicyclo[5.1.0]oct-8-exo-yl) urea, 1,3 bis(bicyclo[6.1.0]non-9-exo-yl)urea, 1,3 bis (bicyclo[7.l.0]dec 10 exo-yl)urea, 1,3 bis(bicyclo [3.1.0]hex-6-endo-yl)urea, 1,3 bis(bicyclo[4.1.0]hept-7- endo-yl)urea, 1,3 bis(bicyclo[5.l.0]oct-8-endo-yl)urea, 1,3 bis(bicyclo[6.1.0]non-9-endo-yl)urea, and 1,3 bis (bicyclo[7.l.0]dec-10-endo-yl)urea; and also the following carbamates of Formula D ethyl bicyclo[3.1.0]hexane-6-exo-carbamate,

ethyl bicyclo [4. l .Olheptane-7-exo-carbamate, ethyl bicyclo [5.1.0] octane-8-exo-carbamate,

ethyl bicyclo[6.1.0]nonane-9-exo-carbamate, ethyl bicyclo [7.1 .0] decane-lO-exo-carbamate, ethyl bicyclo[3.1.0]hexane-6-endo-carbamate, ethyl bicyclo[4.1.0] heptane-7-endo-carbamate, ethyl bicyclo[5.1.0]octane-8-endo-carbamate, ethyl bicyclo[6.1.0]nonane-9-endo-carbamate, and ethyl bicyclo[7.1.0]decane-10-endo-carbamate.

Suitable starting dihalides include 1,5-dichloropentane, 1,5 dibromopentane, 3,3-dimethyl-l,5-diiodopentane, 3- ethyl-3-methyl-1,5-diiodopentane, 1,4 diiodobutane, 1,4- dibromobutane, 2,3-dimethyl-1,4-dibromobutane, and 1,6- diiodohexane.

By reacting these dihalides with the above l-aminocyclopropacycloalkanes, there are obtained 1-exo-piperidino-, exo 4,4-dimethylpiperidino-, 1-exo-4-ethyl-4-methylpiperidino-, 1 exo pyrrolidino-, 1-exo-3,4-dimethylpyrrolidino-, 1 exo hexamethyleneimino-, 1 endo-piperidino-, 1endo-4,4 dimethylpiperidino-, 1 endo 4 ethyl-4- methylpiperidino-, 1 endo pyrrolidino, 1 endo-3,4- dimethylpyrrolidino-, and 1 endo hexamethyleneiminocyclopropacyclohexane, cyclopropacycloheptane, cyclopropacyclooctane, cyclopropacyclononane, and cyclopropacyclodecane, as well as the 1,1'-pentamethylene-, 1,1- (3,3-dimethylpentamethylene)-, 1,1 (3 ethyl 3-methylpentamethylene)-, 1,1'-tetramethylene-, 1,1 (2,3 dimethyltetramethylene)-, and 1,l'-hexamethylene-bis-quaternary ammonium halides, and the 5-halopentyl-, S-halo- 3,3-dimethylpentyl-, 5-halo-3-ethyl-3-methylhexyl, 4-halobutyl-, 4-halo-2,3-dimethylpentyl, and 6-halohexyl-monoquaternary ammonium halides thereof.

The l-(eyclicamino)cyclopropacycloalkanes of Formula I exist either in the protonated or non-protonated forms according to the pH of the environment. When the protonated form is intended the compound is qualified as the acid addition salt; when the non-protonated form is intended it is qualified as the free base. The free bases can be converted to stable acid addition salts by neutralizing the free base with the appropriate acid to below about pH 7.0, and advantageously to about pH 2 to pH 6. Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, thiocyanic, fluosilicic, hexafluoroarsenic, hexafluorophosphoric, acetic, succinic, citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, mucic, camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, 3-phenylsalicylic, 5-phenylsalicylic, 3- methylglutaric, ortho sulfobenzoic, cyclopentanepropionic, 1,Z-cyclohexanedicarboxylic, 4-cyclohexanecarboxylic, octadecenylsuccinic, octenylsuccinic, methanesulfonic, benzenesulfonic, helianthic, Reineckes, dimethyldithiocarbamic, cyclohexylsulfamic, hexadecylsulfamic, octadecylsulfamic, sorbic, monochloroacetic, undecylenic, 4'- hydroxyazobenzene-4-sulfonic, octyldecylsulfuric, picric, benzoic, cinnamic, and like acids.

The acid addition salts can be used for the same purposes as the free base or they can be employed to upgrade the same. For example, the free base can be converted to an insoluble salt, such as the picrate, which can be subjected to purification procedures, for example, solvent extractions and washings, chromatography, fractional liquid-liquid extractions, and crystallization and then used to regenerate the free base form by treatment with alkali or to make a different salt by metathesis. Or the free base can be converted to a water soluble salt, such as the hydrochloride or sulfate, and the aqueous solution of the salt extracted with various water-immiscible solvents before regenerating the free base form by treatment of the thus-extracted acid solution or converted to another salt by metathesis. The free bases can be used as a butter or as an antacid. Ihgwucid-addition salt when condensed with formaldeh de f o u matena utannmmmjlii 42 320 and 2 6 in the acid free bases also make good vehicles for toxic acids. For example, the fluosilicic acid addition salts are useful as mothproofing agents according to US. Patents 1,915,334 and 2,075,359, and the hexafluoroarsenic acid and hexafluorophosphoric acid addition salts are useful as parasiticides according to US. Patents 3,122,536 and 3,122,552.

The compounds of Formula I also form salts with penicillinsf These salts have the same antibacterial activity as the penicillins but diiferent solubility characteristics which make them useful in situations indicated by the special solubility characteristics and in the solution and purification of the penicillins, particularly benzyl penicillin. Said salts can be formed either by neutralization of the free base form of a Formula 1, with the free acid form of a penicillin, or by a metathetical exchange of the anion of an acid addition salt of a Formula I compound, for example, the chloride ion of a hydrochloride, with the anionic form of a penicillin.

The novel free bases of Formula I are useful as catalysts for reactions between isocyanates and active hydrogen compounds, e.g., alcohols and amines, and are es pecially useful as catalysts for the formation of polyurethanes, e.g., polyurethane foams, by interaction of polyisocyanates and polyhydroxy compounds.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting. The parts and percentages are by weight and the solvent ratios are by volume unless otherwise specified.

7 EXAMPLE 1 l-(bicyclo[3.1.0]hexan-6-exo-yl)piperidine hydrochloride (1-exo-piperidinocyclopropacylohexane hydrochloride (A) Ethyl bicyclo[3.1.0]hexane-6-exo-carbamate and 1,3-bis(bicyclo[3.1.0]hex-6-exo-yl)urea Bicyclo[3.1.0]hexane-6-exo-carboxylic acid (6.31 g., 0.05 mole), (Meinwald et al., supra), was dissolved in a mixture of 25 ml. acetone and 10 ml. water and the solution was cooled to -5 C. A solution of 6.32 g. (0.0625 mole) triethylamine in 45 ml. acetone was added slowly, followed by a solution of 6.78 g. (0.0625 mole) ethyl chloroformate in m1. acetone. Stirring was continued for 30 min. Sodium azide (4.88 g. 0.075 mole) was dissolved in 30 ml. water and added dropwise. The mixture was stirred at -5 C. for 2% hr. and then poured into cold saturated sodium chloride solution. The solution was extracted several times with ether. The extract was dried over magnesium sulfate and added to 250 ml. absolute ethanol. The ether was distilled and the remaining ethanolic solution was refluxed for 6 hr. The solvent was evaporated and the residue was treated with ether. The insoluble material was isolated by filtration and washed with ether to give 0.15 g. of 1,3-bis(bicyclo[3.1.0]Ihex-6-exoyl)-urea, M.P. 235240 C. (dec.).

AnaIysis.-Calcd. for C H N O-1/6H O (percent): C, 69.91; H, 9.18; N, 12.55. Found (percent): C, 69.95; H, 9.06; N, 12.50.

The filtrate was concentrated to an oil and the crude ethyl bicyclo[3.1.0]hexane-6-exo-carbamate was used directly in the following step.

(B) Bicyclo[3.1.0]hexan-6-exoamine Hydrochloride A solution of 7.7 g. (0.045 mole) of crude ethyl bicyclo- [3.1.0]hexane-6-exo-carbamate in 100 ml. ethanol and 100 ml. aqueous potassium hydroxide was refluxed under nitrogen for hr. The reaction mixture was distilled until the distillate temperature reached 90 C. The distillate was diluted with 150 ml. ether, dried over magnesium sulfate and distilled through a 24" spinning band column until the head temperature reached 80 C. The oily residue was dissolved in ether and the solution was dried over magnesium sulfate. Addition of ethereal hydrogen chloride precipitated 3.78 g. off-white solid, M.P. 219 C. (dec.). Two crystallizations from methanol/ether gave 3.50 g. (59%) of bicyclo[3.1.0]hexane-6-exo-amine hydrochloride as cream-colored plates, M.P. 221 C. (dec.).

AnaIysis.Calcd. for C H N-HCl (percent): C, 53.93; H, 9.05; N, 10.48; Cl, 26.53. Found (percent): C, 53.34; H, 8.92; N, 10.12; Cl, 26.27.

The yield of the amine can be substantially improved by substituting water for ethanol in the above procedure.

The 1,3-bis(bicyclo[3.1.0]hex-6-exo-yl)urea of part A on treatment with phosgene according to U.S. Patent 3,275,669 is converted to bicyclo[3.1.0]hexan-6-exo-yl isocyanate which on hydrolysis yields bicyclo[3.1.0]hexan-6-exo-amine, which on conversion to the hydrochloride by the procedure given above yields bicyclo[3.1.0]hexan- 6-exo-amine hydrochloride identical with that given above.

N'(bicyclo[3.1.0]hex-6-exo-yl)urea which is useful as a hypoglycemic agent.

(C) 1 (Bicyclo[3.1.0]hexane-6-exo-yl)piperidine Hydrochloride Bicyclo[3.l. ]hexan-6-exo-amine hydrochloride (3.98 g., 0.03 mole) was dissolved in water and the solution was made alkaline with sodium hydroxide. The free amine separated as an oil and was taken up in ether. The ether solution was dried over magnesium sulfate. 1,5-diiodopentane (19.4 g., 0.06 mole) and 8.29 g. (0.0105 mole) potassium carbonate were added and the suspension was gently warmed on the steam bath until most of the ether was evaporated. The residue was heated on the steam bath under nitrogen for 24 hr. Water was added and a yellow solid separated which was removed by filtration, washed with water and ether and not further identified. The filtrate was saturated with sodium chloride and extracted three times with ether. The ether solution was extracted with 0.1 N hydrochloric acid until the extract was acidic. The solution of amine hydrochloride was back-extracted with ether and then made alkaline with sodium hydroxide and saturated with sodium chloride. The amine was extracted into ether and the solution was dried over magnesium sulfate. Addition of ethereal hydrogen chloride gave 1.75 g. of 1-(bicyclo[3.1.0]- hexan-6-exo-yl)piperidine hydrochloride as a yellow solid, M.P. 240 C. (dec.). Two crystallizations from methanol/ether yielded 1.43 g. (24%) white crystals, M.P. 245 C. (dec.).

AnaIysis.-Calcd. for C H N-HCl (percent): C, 65.50; H, 9.99; N, 6.94; Cl, 17.57. Found (percent): C, 65.37; H, 10.18; N, 7.02; Cl, 17.34.

EXAMPLE 2 (A) 1-(bicyclo[3.l.0]hexan-6-exo-yl)pyrrolidine and 1,1 tetramethylene bis (1 bicyclo[3.1.0]hex-6-cxo- Bicyclo[3.1.0]hexan-6-exo-amine hydrochloride (15.1 g., 0.112 mole) was dissolved in water and the solution was made basic with sodium hydroxide. The free amine separated as an oil and was taken up in ether. The ether solution was dried over magnesium sulfate. The drying agent was filtered and most of the ether was removed by gently warming the filtrate on the steam bath. Absolute ethanol ml.), 34.7 g. (0.112 mole) 1-4-diiodobutane, and 31.0 g. (0.22 mole) potassium carbonate were added to the residue and the suspension was stirred under nitrogen on the steam bath for 7 hours. Ethanol (50 ml.) was distilled and 100 ml. water was added. The suspension was extracted with three 75-ml. portions of ether and the extract was dried over magnesium sulfate (saved the water layer which contained some solid). The ether was evaporated and the residue was distilled through a 24" spinning band column. After a 1.0 g. forerun, the product, 1-(bicyclo[3.1.0]hexan-6-exo-yl)- pyrrolidine, was collected as a colorless oil; 6.15 g. (36%), B.P. 82 C. (13 mm.).

Analysis.-Calcd. for C H N (percent): C, 79.40; H, 11.34; N, 9.26. Found (percent): C, 79.40; H, 11.35; N, 9.97.

A solid was filtered from the above water layer and washed with water. Crystallization from about 200 ml. absolute ethanol gave 3.12 g of 1,1'-tetramethylene-bis- (1-bicyclo[3.l.0]-hex-6 exo-yl)pyrrolidinium iodide as yellow needles, M.P. 257 C. (dec.).

Analysis.--Calcd. for q H N l (percent): C, 47.07; H, 6.91; N, 4.58; I, 41.44. Found (percent): C, 47.15; H, 6.87; N, 4.57; I, 41.54.

(B) 1-(bicyclo[3.1.0]hexan-6-exo-yl)pyrrolidine oxalate.

all...

A solution of 6.15 g. (0.041 mole) of l-(bicyclo[3.1.0]-hexan-6-exo-yl)pyrrolidine in ether was added to an ether solution of 3.69 g. (0.041 mole) oxalic acid. The resulting solid was filtered and washed with ether. Crystallization from 1:1 ethanol/ether gave 6.92 g. (70%) of 1-(bicyclo[3.1.0]hexan-6-exo-yl)pyrrolidine oxalate as white plates, M.P. l79-l81 C. (dec.).

Analysis.-Calcd. for C l-l N'C H o (percent). C, 59.73; H, 7.94; N, 581. Found (percent): C, 59.88; H, 7.93; N, 5.62.

EXAMPLE 3 l-(bicyclo [3 1 .0] hexan-6-endo-yl piperidine hydrochloride (A) 1,3-bis(bicyclo[3.l.0]hex-6-endo-yl)urea ethyl bicyclo[3.1.0]hexane-6-endo-carbamate Bicyclo[3.1.0]hexane-6-endo-carboxylic acid (6.31 g., 0.05 mole), (Meinwald et al., supra), was dissolved in a mixture of 25 ml. acetone and 10 ml. water and the solution was cooled to 5 C. A solution of 6.32 g. (0.0625 mole) triethylamine-in 45 ml. acetone was added slowly, followed by a solution of 6.78 g. (0.0625 mole) ethyl chloroformate in ml. acetone. Stirring was continued for 30 minutes. Sodium azide (4.88 g., 0.075 mole) was dissolved in 30 ml. water and added dropwise. The mixture was stirred at 5 C. for 2% hr. and then poured into cold saturated sodium chloride solution. The solution was extracted several times with ether. The extract was dried over magnesium sulfate and added to 250 ml. absolute ethanol. The ether was distilled and the remaining ethanolic solution was refluxed for 6 hr. The solvent was evaporated and the oily residue crystallized partially on cooling. Ether was added and the insoluble material was isolated by filtration and washed with ether to give 0.17 g. of l,3-bis-(bicyclo[3.1.0lhex-6-endoyl)-urea. M.P. 200-205 C. (dec.).

AMIYSiSr-CfllCd. for CmHgoNgO'l/6Hz0 (percent): C, 69.91; H, 9.18; N, 12.55. Found (percent): C, 69.52; H, 8.96; N, 12.60.

The filtrate was concentrated to an oil which was treated with a small amount of Skellysolve B (technical hexane) and cooled in a solid carbon dioxide-acetone bath. Three crops of crystals were obtained which melted 38-46 C. Crystallization from Skellysolve B gave 2.60 g. (31%) ethyl bicyclo[3.1.0]hexane 6 endo carbamate as colorless needles, M.P. 4648 C.

AnaIysis.-Calcd. for C H NO (percent): C, 63.88; H, 8.94; N, 828. Found (percent): C, 63.93; H, 9.08; N, 8.55.

10 (B) Bicyclo[3.1.0]hexan 6 endo amine hydrochloride The mother liquors from the crystallization of ethyl bicyclo[3.l.0]hexane 6 endo carbamate were combined and the Skellysolve B was evaporated. The residual oil was dissolved in 50 ml. ethanol and 50 ml. 20% aqueous potassium hydroxide and refluxed for 30 hr. The reaction mixture was distilled and 60 ml. distillate was collected, containing most of the product. The distillate was diluted with an equal volume of ether and this solution was dried twice over magnesium sulfate. The solvents were distilled through a 24" spinning band column. The oily residue was dissolved in ether and the solution was dried over magnesium sulfate. Addition of ethereal hydrogen chloride precipitated 0.95 g. yellow solid, M.P. C. (dec.). Crystallization from ethanol/ether gave 0.90 g. bicyclo[3.1.0]hexan 6 endo amine hydrochloride as yellow plates, M.P. 189 C. (dec.).

Analysis.-Calcd. for C H N-HCI (percent): C, 53.93; H, 9.05; N, 10.48; Cl, 26.53. Found (percent): C, 54.21; H, 9.31;N, 10.68; Cl, 26.34.

The yield of the amine can be substantially improved by substituting water for ethanol in the above reaction mixture.

The 1,3 bis(bicyclo[3.1.0]hex 6-endo-yl) urea of this example, part A on treatment with phosgene according to U.S. Pat. 3,275,669 is converted to bicyclo[3.1.0]hexan- 6-endo-yl isocyanate which on hydrolysis yields bicyclo [3.1.0]hexan-6-endo-amine, which on conversion to the hydrochloride by the procedure given above yields bicyclo [3.l.0]hexan-6-endoamine hydrochloride identical with that given above. If desired, the bicyclo[3.1.0]hexan-6- endo-yl isocyanate can be recycled to the ethanolic solution of part A prior to reflux. The isocyanate can also be reacted with 4 methylbenzenesulfonamide according to Example 15 of U.S. Pat. 2,968,158 to form N-(4 methylbenzenesulfonyl) N (bicyclo[3.1.0]hex 6-endo-yl) urea which is useful as a hypoglycemic agent.

(C) 1 (bicycl0[3.1.0]hexan 6 endO-yDpiperidine hydrochloride Bicyclo[3.1.0]hexan 6 endo amine hydrochloride (0.70 g., 0.00525 mole) was dissolved in water and the solution was made alkaline with sodium hydroxide. The free amine separated as an oil and was taken up in ether. The ether solution was dried over magnesium sulfate. 1,5-diiodopentane (3.40 g., 0.0105 mole) and 1.45 g. (0.0105 mole) potassium carbonate were added and the suspension was gently warmed on the steam bath until most of the ether was evaporated. The residue was heated on the steam bath under nitrogen for 24 hr. Water was added, the solution was saturated with sodium chloride and extracted with three 15-ml. portions of ether. The ether solution was extracted with 0.1 N hydrochloric acid until the extract was acidic. The solution of amine hydrochloride was back-extracted with ether and then made alkaline with sodium hydroxide and saturated with sodium chloride. The amine was extracted into ether (three 20-ml. portions) and the solution was dried over magnesium sulfate. Addition of ethereal hydrogen chloride gave a solid which was dissolved in methanol and precipitated by the addition of ether to give 0.68 g. (64% 1-(bicyclo[3.1.0]hexanl 1 6-endo-yl)piperidine hydrochloride as colorless plates, M.P. 212 (dec.).

EXAMPLE4 (A) 1-(bicyclo[3.1.0]hexan-6-endo-yl)pyrrolidine Bicyclo[3.1.0]hexan 6 endo amine hydrochloride 17.1 g., 0.128 mole) was dissolved in water and the solution was made alkaline with sodium hydroxide. The free amine separated as an oil and was taken up in ether. The ether solution was dried over magnesium sulfate. The drying agent was filtered and most of the ether was removed by gently warming the filtrate on the steam bath. Absolute ethanol (100 ml.), 39.7 g. (0.128 mole) 1,4-diiodobutane, and 35.4 g. (0.256 mole) potassium carbonate were added to the residue and the suspension was stirred under nitrogen on the steam bath for 5 hours. Ethanol (50 ml.) was distilled and 100 ml. water was added. The solution was extracted with three 75ml. portions of ether and the extract was dried over magnesium sulfate. The ether was evaporated and the residue was distilled through a 24 spinning band column. After a small forerun, the product, 1 (bicyclo[3.1.01hexan 6 endoyl)pyrrolidine, was collected as a colorless oil; 14.3 g. (74% B.P. 75-77 C. (12 mm.).

AnaIysis.-Calcd. for C H N (percent): C, 79.40; H, 11.34; N, 9.26. Found (percent): C, 78.66, 78.63; H, 11.24, 11.07; N. 9.18.

(B) l-(bicyclo[3.1.0]hexan-6-endo-y1)pyrrolidine oxalate O (Y O A solution of 14.3 g. (0.093 mole) of 1-(bicyclo[3.l.0] hexan 6 endo yl) pyrrolidine in ether was added to an ether solution of 8.37 g. (0.093 mole) oxalic acid. The resulting solid was filtered and washed with ether. Two crystallizations from about 400 ml. 1:1 ethanol/ether gave 13.1 g. of 1 (bicyclo[3.1.01hexan 6-endo-yl)pyrrolidine oxalate as white needles, M.-P. 115-120 C., cloudy melt.

Analysis.--Calcd. for (C1oH 7N)2'(C3H3O )3 (percent): C, 54.53; H, 7.04; N, 4.89. Found (percent): C, 54.91; H, 7.09; N, 4.83.

EXAMPLE Conversion of bicyclo [3 .l.0]hexane-6-endocarboxylic acid to the exo form (A) Methyl bicyclo[3.1.0] hexane 6 endo carboxyl- 816 qua-whoa);

- Bicyclo [3.1.0]hexane-6 endo-carboxylic acid (189 g., 0.15 mole) was added in small portions to an ethereal solution of diazomethane, prepared from 44.1 g. (0.3 mole) N-methyl-N-nitroso-N' nitroguauidine. The reaction mixture was allowed to stand overnight and the excess diazomethane was destroyed by the addition of acetic acid. Half the ether was distilled and the concentrated solution was extracted twice with aqueous sodium CH O-C o Methyl bicyclo[3.1.01hexane 6 endocarboxylate (18.3 g., 0.13 mole) was added to a solution of 9.0 g. (0.39 mole) sodium in 250 m1. absolute ethanol and refluxed for 24 hr. Water ml.) was added and refluxing was continued for 4 hr. The ethanol was distilled and the residue was washed twice with ether. The aqueous phase was acdified with concentrated hydrochloric acid and refrigerated. Yellow crystals separated and were filtered and washed with water. The crude product was dissolved in Skellysolve B. The organic layer was separated from a small water layer and treated with decolorizing carbon. The resulting colorless solution was concentrated to about 40 ml. and refrigerated to yield 12.4 g. (76%) of bicyclo[3.1.0]hexane 6 exo-carboxylic acid as large colorless plates, M.P. 59.5-61.5 C.

The exo form can be isomerized to the endo form by the same procedure. The yields are lower, however, because the equilibrium favors the exo form.

EDiAMPLE 6 1-(bicyclo[3.1.0]hexan 6 exo-yl)piperidine hydrochloride and exo-1-bicyclo[3.1.0]hex 6 yl-1-(5-iodopentyl)piperidinium iodide sgfQ Bicyclo[3.1.0]hexan 6 exo-amine hydrochloride (13.4 g., 0.1 mole) was dissolved in water and the solution was made alkaline with sodium hydroxide. The free amine was taken up in ether and the ether solution was dried over magnesium sulfate. The ether was evaporated by gentle warming on the steam bath. 1,5-diiodopentane (64.8 g., 0.2 mole), potassium carbonate (27.6 g., 0.2 mole), and 100 ml. absolute ethanol were added and the mixture was stirred on the steam bath under nitrogen for 22 hrs. Most of the ethanol was distilled and water and ether were added. A material, insoluble in both phases, separated and was collected. Crystallization from ethanol gave exo-1-bicyclo[3.1.0]hex 6 yl-1-(5-iodopentyl)piperidinium iodide (7.45 g.) as oil-white plates, M.P. l47-150 C.

Analysis.-Calcd. for C I-I I N (percent): C, 39.28; H, 5.97; N, 2.86; I, 51.88. Found (percent): C, 40.07; H, 6.10; N, 2.72; I, 50.60.

1-(bicyclo[3.1.0]hexane 6 exo-yl)piperidine hydrochloride, as characterized in Example 1, part C, was isolated in 61% yield from the ether layer by the procedure of Example 1, part C.

We claim:

1. A compound of the formula wherein R is polymethylene of 3 to 7 carbon atoms, 15

R is alkyl of not more than 2 carbon atoms, n is zero or an integer not greater than 2, R, is lower alkylene of from 2 to 6 carbon atoms, X is halogen and Y is an anion.

3. A compound of claim 2 wherein R: is selected from the group consisting of tetramethylene, pentamethylene 20 and hexamethylene.

4. A compound according to claim 3 wherein R is trimethylene and n is zero, R, is pentamethylene, and both X and Y are iodine.

14 the group consisting of tetramethylene, pentamethylene and hexamethylene.

6. A compound of claim 1 wherein R is trimethyiene, n is zero, R, is tetramethylene and X is iodine.

References Cited UNITED STATES PATENTS 3,164,601 1/1965 Thesing et a1 260-2947 3,258,469 6/ 1966 Blanchard et a1. 260-326.8

OTHER REFERENCES Shirley, Organic Chemistry, Holt, Rinehart and Winston, New York, p. 440.

Elderfield, Heterocyclic Compounds, vol. 1, John Wiley & Sons, Inc., New York (1950), pp. 62, 63, 80 and 81.

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl. X.R. 252-149; 260-25, 75, 77.5, 239, 239.1, 271, 293.4, 294,

5. A compound of claim 1 wherein R, is selected from 25 326.8, 453, 468, 553; 424-244, 267, 274

UNITED STATES PATENT OFFICE 2252" CERTIFICATE OF CORRECTION Patent No. 3,5 33 Dated December 97 Invent Jacob Szmusz kovicz and E I i sabeth Ce rda It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

CoIumn l, I I ne 2}, for "2X" read 2X Column 1, I i 56, for "2X" read 2X' Column 4, I ine 75, for 'cyc Iopropacy Ic Ioa I ka nes" read cyc Iop ropacycioa I ka nes Co Iumn 6, I Ine 56, for so Iution" read isoIati on Co Iun 6, I ine 59, for "of a P0 rmu Ia l read of a compound of F0 rmu Ia l Co Iumn 7, I ine 3, for "pipe ri dinocyc Iop ropacy Iohexane Hyd roch Ioride" read pipe ridi nocyci o ropacyc Iohexane Hyd roch Ioride Coiumn 7, I i ne 38, for 'exoami ne" re exo-ami ne Coiumn 8, I I ne 3, for "hexane" read hexar Co Iumn 9, I I ne 27, for "N, 581 read N, 5.81 Column E I i ne 74 for "N, 828." read N, 8.28 CoIumn 11, I i ne 65 for "189 read 18.9 g Co Iumn l2 I ine 22, for "acdi Fied read acidified Signed and sealed this 29th day of August 1972.

(SEAL) Attest:

ED -iAHD MJ LETCHEILJR. ROBERT GOTTSCHALK Attesting, Officer Commissioner of Pater 

